反应详情

A solution of tert-butyl 4-(3-(4-(3,4-difluoro-2-(trifluoro-methyl)phenyl)piperidine-1-carbonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole-5-carbonyl)piperazine-1-carboxylate (47 mg, 0.077 mmol) in anhydrous CH2Cl2 (1.5 mL) was cooled to 0° C. under an atmosphere of N2 and treated with TFA (1.5 mL). When the addition was complete, the cooling bath was removed and the reaction stirred at room temperature for 1 h. After this time, the mixture was concentrated to dryness under reduced pressure, diluted in CH2Cl2 (100 mL) and washed with 2 M aqueous NaOH (2×50 mL). The organic layer was dried over Na2SO4 and the drying agent removed by filtration. The filtrate was concentrated to dryness under reduced pressure and the resulting residue chromatographed over silica gel (Isco CombiFlash Rf unit, 120 g Redisep column, 0% to 40% CH3OH in CH2Cl2). The combined column fractions were concentrated to dryness under reduced pressure and found to contain residual TFA (˜17%). The resulting residue (21 mg) was diluted in a mixture of CH2Cl2 (5 mL) and CH3OH (1 mL), treated with MP-carbonate and stirred at room temperature for 2 h. After this time the mixture was filtered and the filtrate concentrated to dryness under reduced pressure to provide (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(piperazine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone as a white solid (13 mg, 33%): mp 153-155° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.20 (br s, 1H), 7.75 (dd, J=18.0, 9.0 Hz, 1H), 7.55-7.52 (m, 1H), 4.65-4.51 (m, 6H), 3.24-3.22 (m, 2H), 3.14 (t, J=5.0 Hz, 4H), 2.96-2.80 (m, 1H), 2.70-2.68 (m, 3H), 2.32-2.22 (m, 1H), 1.79-1.70 (m, 4H), 1 proton not readily observed; ESI MS m/z 513 [M+H].

1. additionWhen the addition
2. customthe cooling bath was removed
3. concentrationAfter this time, the mixture was concentrated to dryness under reduced pressure
4. additiondiluted in CH2Cl2 (100 mL)
5. washwashed with 2 M aqueous NaOH (2×50 mL)
6. dry with materialThe organic layer was dried over Na2SO4
7. customthe drying agent removed by filtration
8. concentrationThe filtrate was concentrated to dryness under reduced pressure
9. customthe resulting residue chromatographed over silica gel (Isco CombiFlash Rf unit, 120 g Redisep column, 0% to 40% CH3OH in CH2Cl2)
10. concentrationThe combined column fractions were concentrated to dryness under reduced pressure
11. additionThe resulting residue (21 mg) was diluted in a mixture of CH2Cl2 (5 mL) and CH3OH (1 mL)
12. additiontreated with MP-carbonate
13. stirringstirred at room temperature for 2 h
14. filtrationAfter this time the mixture was filtered
15. concentrationthe filtrate concentrated to dryness under reduced pressure